Version of FDG Detectable by Single-Photon Emission Computed Tomography

Abstract

A compound comprising a metal chelate linked to a hexose carrier for use as a metallopharmaceutical diagnostic or therapeutic agent is provided. The compound is suitable for imaging by single-photon emission computed tomography, computer assisted tomography, magnetic resonance spectroscopy, magnetic resonance imaging, positron emission tomography, fluorescence imaging or x-ray.

Description

FIELD OF THE INVENTION

[0001] The present invention is generally directed to a metal chelate linked to a hexose carrier for use as a metallopharmaceutical diagnostic or therapeutic agent.BACKGROUND OF THE INVENTION

[0002] The rate of glucose metabolism by a living cell is known to be a useful indicator of a variety of abnormal physiological conditions, particularly in human patients. Included among these conditions are various forms of cancer, coronary artery disease, brain tumors and epilepsy. The diagnosis and locale determination of these conditions has been made possible by sophisticated imaging techniques that identify cells which are demonstrating abnormally high or low rates of glucose intake.

[0003] Until now, glucose imaging has been performed by positron-emission tomography (PET) with glucose analogs such as carbon-11-labeled glucose and 18F-labeled 2-deoxy-2-fluoro-D-glucose and its isomer 18F-labeled 3-deoxy-3-fluoro-D-glucose (collectively referred to as “FDG”). FDG, upon adm...

Examples

example 1

[0098]Preparation of the metallopharmaceutical compound DOTA 6-aminoglucose of formula (11):

[0099]DO3A-tris(tert-butyl) ester (A) is alkylated with benzyl 2-(2-bromoacetamido)ethylcarbamate (B) in acetontrile and sodium bicarbonate. The carbenzoxy group is removed by hydrogenolysis and the resulting free amine (D) is alkylated by 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (E). The glucose conjugate, (F), may be deprotected sequentially via saponification and treatment with trifluoroacetic acid to give the free chelator (11), probably as the TFA-salt.

example 2

[0100]Preparation of the metallopharmaceutical compound iminodiacetic acid 6-aminoglucose of formula (12):

[0101]Tert-butyl 2,2′-(2-aminoethylazanediyl)diacetate (A) is treated with 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (B) under dilute conditions with an organic base such as triethylamine. The product (C) may be isolated via preparative chromatography and deprotected sequentially via saponification and treatment with trifluoroacetic acid to give the free chelator (12), probably as the TFA-salt.

example 3

[0102]Preparation of the metallopharmaceutical compound DTPA-6-aminoglucose of formula (13):

[0103]Mono(carbobenzoxy)ethylenediamine (A) may be mono-alkylated with 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (B) under dilute conditions with an organic base such as triethylamine. Following hydrogenolysis, to unmask the primary amine (D), and acetylation with an excess of DTPA-bis(anhydride) (E), to give the mono-acylate (F), the protected intermediate may be purified by reverse phase chromatography. Finally, saponification with sodium hydroxide and aqueous methanol, will provide the free glucosamine-DTPA (13).

FIELD OF THE INVENTION

[0001] The present invention is generally directed to a metal chelate linked to a hexose carrier for use as a metallopharmaceutical diagnostic or therapeutic agent.BACKGROUND OF THE INVENTION

[0002] The rate of glucose metabolism by a living cell is known to be a useful indicator of a variety of abnormal physiological conditions, particularly in human patients. Included among these conditions are various forms of cancer, coronary artery disease, brain tumors and epilepsy. The diagnosis and locale determination of these conditions has been made possible by sophisticated imaging techniques that identify cells which are demonstrating abnormally high or low rates of glucose intake.

[0003] Until now, glucose imaging has been performed by positron-emission tomography (PET) with glucose analogs such as carbon-11-labeled glucose and 18F-labeled 2-deoxy-2-fluoro-D-glucose and its isomer 18F-labeled 3-deoxy-3-fluoro-D-glucose (collectively referred to as “FDG”). FDG, upon adm...

Examples

example 1

[0098]Preparation of the metallopharmaceutical compound DOTA 6-aminoglucose of formula (11):

[0099]DO3A-tris(tert-butyl) ester (A) is alkylated with benzyl 2-(2-bromoacetamido)ethylcarbamate (B) in acetontrile and sodium bicarbonate. The carbenzoxy group is removed by hydrogenolysis and the resulting free amine (D) is alkylated by 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (E). The glucose conjugate, (F), may be deprotected sequentially via saponification and treatment with trifluoroacetic acid to give the free chelator (11), probably as the TFA-salt.

example 2

[0100]Preparation of the metallopharmaceutical compound iminodiacetic acid 6-aminoglucose of formula (12):

[0101]Tert-butyl 2,2′-(2-aminoethylazanediyl)diacetate (A) is treated with 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (B) under dilute conditions with an organic base such as triethylamine. The product (C) may be isolated via preparative chromatography and deprotected sequentially via saponification and treatment with trifluoroacetic acid to give the free chelator (12), probably as the TFA-salt.

example 3

[0102]Preparation of the metallopharmaceutical compound DTPA-6-aminoglucose of formula (13):

[0103]Mono(carbobenzoxy)ethylenediamine (A) may be mono-alkylated with 6-tosyl-2,3,4,5-tetra-O-acetyl glucose (B) under dilute conditions with an organic base such as triethylamine. Following hydrogenolysis, to unmask the primary amine (D), and acetylation with an excess of DTPA-bis(anhydride) (E), to give the mono-acylate (F), the protected intermediate may be purified by reverse phase chromatography. Finally, saponification with sodium hydroxide and aqueous methanol, will provide the free glucosamine-DTPA (13).

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